National Institute
on Alcohol Abuse and Alcoholism No. 21 PH 345 July 1993

Alcohol and Cancer

Cancer kills an estimated
526,000 Americans yearly, second only to heart disease (1). Cancers of the
lung, large bowel, and breast are the most common in the United States. Considerable
evidence suggests a connection between heavy alcohol consumption and increased
risk for cancer, with an estimated 2 to 4 percent of all cancer cases thought
to be caused either directly or indirectly by alcohol (2).

A strong association
exists between alcohol use and cancers of the esophagus, pharynx, and mouth,
whereas a more controversial association links alcohol with liver, breast,
and colorectal cancers. Together, these cancers kill more than 125,000 people
annually in the United States (1). The following sections discuss alcohol's
role in these cancers.

What Is Cancer?

Cancer is a group of
diseases characterized by cells that grow out of control; in many cases, they
form masses of cells, or tumors, that infiltrate, crowd out, and destroy normal
tissue. Although the body strictly regulates normal cells to grow within the
confines of tissues, cancer cells reproduce independently, uninhibited by
tissue boundaries. Cancer develops in three stages: initiation, promotion,
and progression. Cancer-causing agents, known as carcinogens, can contribute
to the first two stages.

Cancer initiation
occurs when a cell's DNA (the substance that genes are made of) is irreversibly
changed so that, once triggered to divide, the cell will reproduce indefinitely.
The "change" involves mutations to the cell's genes that can occur spontaneously
or can be induced by a carcinogen. In some cancers, it has been shown that
the mutations occur in oncogenes, genes that normally promote cell division,
or in suppressor genes, genes that normally suppress cell division. Thus,
it is believed that cancer-causing mutations result in overpromotion or undersuppression
of cell reproduction. During cancer promotion, the initiated cell is stimulated
to divide. The stimulus can be natural, as when tissue damage requires proliferation
of new cells, or it can be caused by a carcinogen. During cancer progression,
tumors produced by the replicating mass of cells metastasize, or spread, from
the initial or primary tumor to other parts of the body, forming secondary
cancers.

Alcohol's Link
to Cancer

Two types of research
link alcohol and cancer. Epidemiologic research has shown a dose-dependent
association between alcohol consumption and certain types of cancer; as alcohol
consumption increases, so does risk of developing certain cancers. More tenuous
results have come from research into the mechanism by which alcohol could
contribute to cancer development.

Epidemiologic Research

The strongest link between
alcohol and cancer involves cancers of the upper digestive tract, including
the esophagus, the mouth, the pharynx, and the larynx (3). Less consistent
data link alcohol consumption and cancers of the liver, breast, and colon
(3).

Upper digestive
tract. Chronic heavy drinkers have a higher incidence of esophageal
cancer than does the general population. The risk appears to increase as alcohol
consumption increases (4-6). An estimated 75 percent of esophageal cancers
in the United States are attributable to chronic, excessive alcohol consumption
(7).

Nearly 50 percent
of cancers of the mouth, pharynx, and larynx are associated with heavy drinking
(7). People who drink large quantities of alcohol over time have an increased
risk of these cancers as compared with abstainers (8,9). If they drink and
smok e, the increase in risk is even more dramatic (5,6).

Liver.
Prolonged, heavy drinking has been associated in many cases with primary liver
cancer. However, it is liver cirrhosis, whether caused by alcohol or another
factor, that is thought to induce the cancer (10,11). In areas of Africa and
Asia, liver cancer afflicts 50 or more people per 100,000 per year, usually
associated with cirrhosis caused by hepatitis viruses. In the United States,
liver cancer is relatively uncommon, afflicting approximately 2 people per
100,000, but excessive alcohol consumption is linked to as many as 36 percent
of these cases by some investigators (2,12).

The association
between alcohol use and liver cancer is difficult to interpret, because liver
cirrhosis and hepatitis B and C virus infections often confound data (13).
Studies of the interactions between alcohol, hepatitis viruses, and cirrhosis
will help clarify these associations with liver cancer (see below).

Breast.
Chronic alcohol consumption has been associated with a small (averaging 10
percent) increase in a woman's risk of breast cancer (14-17). According to
these studies, the risk appears to increase as the quantity and duration of
alcohol consumption increases. Other studies, however, have found no evidence
of such a link (18-20).

The inconsistency
and weakness of epidemiologic findings suggest that a third confounding factor,
such as nutrition, may be responsible for the link between alcohol and breast
cancer (15). However, studies that adjusted for dietary factors such as fat
intake found that the association between alcohol and breast cancer remained
(14,21,22).

Recent studies
suggest that alcohol may play an indirect role in the development of breast
cancer. These studies indicate that alcohol increases estrogen levels in premenopausal
women, which, in turn, may promote breast cancer (23).

Colon.
Epidemiologic studies have found a small but consistent dose-dependent association
between alcohol consumption and colorectal cancer (15,24), even when controlling
for fiber and other dietary factors (15,25,26). Despite the large number of
studies, however, causality cannot be determined from the available data.

Other cancers.
A few studies have linked chronic heavy drinking with cancers of the stomach,
pancreas, and lungs (3). However, the association is consistently weak and
the majority of studies have found no association (3).

Mechanisms of Alcohol-Related
Cancers

The epidemiologic data
provide little insight into whether or how alcohol increases the risk for
various cancers. For some cancers, such as mouth and esophageal, alcohol is
thought to play a direct causal role. For others, such as liver and breast
cancers, alcohol is thought to play an indirect role by enhancing mechanisms
that may cause cancer. Studies looking at these direct and indirect mechanisms
may shed light on alcohol's role in developing cancers.

Oncogenes.
Preliminary studies show that alcohol may affect cancer development at the
genetic level by affecting oncogenes at the initiation and promotion stages
of cancer. It has been suggested that acetaldehyde, a product of alcohol metabolism,
impairs a cell's natural ability to repair its DNA, resulting in a greater
likelihood that mutations causing cancer initiation will occur (27). It has
recently been suggested that alcohol exposure may result in overexpression
of certain oncogenes in human cells and, thereby, trigger cancer promotion
(28).

Alcohol as
a cocarcinogen. Although there is no evidence that alcohol itself
is a carcinogen, alcohol may act as a cocarcinogen by enhancing the carcinogenic
effects of other chemicals. For example, studies indicate that alcohol enhances
tobacco's abil ity to stimulate tumor formation in rats (29). In humans, the
risk for mouth, tracheal, and esophageal cancer is 35 times greater for people
who both smoke and drink than for people who neither smoke nor drink (30),
implying a cocarcinogenic interaction between alcohol and tobacco-related
carcinogens (29).

Alcohol's cocarcinogenic
effect may be explained by its interaction with certain enzymes. Some enzymes
that normally help to detoxify substances that enter the body can also increase
the toxicity of some carcinogens. One of these enzymes is called cytochrome
P-450 (31,32). Dietary alcohol is able to induce cytochrome P-450 in the liver,
lungs, esophagus, and intestines (29,33), where alcohol-associated cancers
occur. Subsequently, carcinogens such as those from tobacco and diet can become
more potent as they, too, pass through the esophagus, lungs, intestines, and
liver and encounter the activated enzyme (29,33).

Nutrition.
Chronic alcohol abuse may result in abnormalities in the way the body processes
nutrients and may subsequently promote certain types of cancer. Reduced levels
of iron, zinc, vitamin E, and some of the B vitamins, common in heavy drinkers,
have been experimentally associated with some cancers (29). Also, levels of
vitamin A, hypothesized to have anticancer properties (34), are severely depressed
in the liver and esophagus of rats during chronic alcohol consumption (35-37).

A recent study
indicates that as few as two drinks per day negates any beneficial effects
of a "correct" diet on decreasing risk of colon cancer (38). Although the
study suggests that a diet high in folic acid, a B vitamin found in fresh
fruits and vegetables, decreases the risk for colon cancer, it also warns
that alcohol consumption may counter this protective action and increase the
risk for colon cancer by reducing folic acid levels.

Mechanisms
of liver cancer. The possible role of alcohol in the development of
liver cancer is incompletely understood. In Asia and Africa, hepatitis B virus
infection is thought to cause most liver cancer; the association is less frequent
in the United States. Eighty percent of patients with liver cancer also have
cirrhosis (39), and between 27 and 80 percent test positive for hepatitis
B or C infection (40). The chronic heavy drinking that causes liver cirrhosis
might exacerbate cirrhosis caused independently by the hepatitis B or C viruses.
Some studies indicate that alcohol consumption hastens the development of
liver cancer in patients with hepatitis C infection (41), whereas others indicate
that alcohol has no compounding effect in such patients (42).

Suppression
of immune response. Alcoholism has been associated with suppression
of the human immune system. Immune suppression makes chronic alcohol abusers
more susceptible to various infectious diseases and, theoretically, to cancer
(43).

Summary

Although epidemiologic
studies have found a clear association between alcohol consumption and development
of certain types of cancer, study findings are often inconsistent and may
vary by country and by type of cancer. The key to understanding the association
lies in research designed to decipher how alcohol may promote cancer. Such
studies examine
alcohol's metabolic effects at the cellular and genetic levels. Research examining
the ways in which alcohol may induce cancers has found some potential mechanisms,
the most promising of which implicates oncogenes.

Alcohol and Cancer--A
Commentary by
NIAAA Director Enoch Gordis, M.D.

As can be seen from this
Alcohol Alert, the evidence for alcohol's role in promoting some cancers
(e.g., cancers of the mouth and throat) is stronger than the evidence linking
alcohol use to other cancers, such as breast cancer. Public health policy
should reflect the str ength of the evidence of alcohol's role in promoting
various cancers. Convincing evidence of
alcohol's effects on common cancers--even when these effects are minor--has
important public health implications. However, it is equally important that
the public not be subjected to undue alarm when evidence for an increased
risk for cancer due to alcohol use is weak or inconclusive.

ACKNOWLEDGMENT:
The National Institute on Alcohol Abuse and Alcoholism wishes to acknowledge
the valuable contributions of Edward Tabor, M.D., associate director for biological
carcinogenesis at the National Cancer Institute, to the development of this
Alcohol Alert.

U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES

Public Health Service
* National Institutes of Health
Updated: October 2000